Autoimmunities
Abstract
Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory autoimmune disorders of the CNS. Immunoglobulin G autoantibodies targeting the aquaporin-4 water channel (AQP4-IgG) are the pathogenic effector of NMOSD. Dysregulated T follicular helper (Tfh) cells have been implicated in the loss of B-cell tolerance in autoimmune diseases. The contribution of Tfh cells to disease activity and the therapeutic potential of targeting these cells in NMOSD remain unclear. Here, we established an autoimmune model of NMOSD by immunizing mice against AQP4 via in vivo electroporation. After AQP4 immunization, mice displayed AQP4 autoantibodies in the blood circulation, blood-brain barrier disruption, and IgG infiltration in the spinal cord parenchyma. Moreover, AQP4 immunization induced motor impairments and NMOSD-like pathologies including astrocytopathy, demyelination, axonal loss, and microglia activation. These were associated with increased splenic Tfh, T helper 1 (Th1) and T helper 17 (Th17) cells, memory B cells and plasma cell. AQP4-deficient mice did not displayed motor impairments and NMOSD-like pathologies after AQP4 immunization. Importantly, abrogating inducible costimulator (ICOS)/inducible costimulator ligand (ICOS-L) signalling using anti-ICOS-L antibody depleted Tfh cells and suppressed the response of Th1 and Th17 cells, memory B cells, and plasma cells in AQP4-immunized mice. These findings were associated with ameliorated motor impairments and spinal cord pathologies. This study suggests a role of Tfh cells in the pathophysiology of NMOSD in a novel mouse model with AQP4 autoimmunity. It also provides an animal model for further investigating the immunological mechanisms underlying AQP4 autoimmunity, and for developing novel therapeutic interventions targeting the autoimmune reactions in NMOSD.
Authors
Leung-Wah Yick, Oscar Ka-Fai Ma, Ethel Yin-Ying Chan, Krystal Xiwing Yau, Jason Shing-Cheong Kwan, Koon-Ho Chan
Abstract
A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCA) found an association between proteinase-3 (PR3) ANCA and a single-nucleotide polymorphism (SNP) (rs62132293) upstream of PRTN3, encoding PR3. The variant (G-allele) was shown to be an eQTL in healthy controls, but the clinical impact remains unknown. Longitudinally followed ANCA patients(n=401) and healthy controls(n=130) were genotyped. Gene expression was quantified by RT-qPCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Kaplan-Meier estimates and log rank test were used for clinical outcomes. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared to non-carriers (C/G vs. C/C and G/G vs. C/C, p=0.012 and p=0.001, respectively, effect size 0.24). Healthy controls had low PRTN3 regardless of genotype. MPO expression did not differ by genotype. PRTN3 (message) correlated with circulating PR3 (r=0.36, p<0.0005) and variant carriers had higher plasma PR3 compared to non-carriers (p=0.041). Among variant carriers, there was a 1.66-fold increased risk of relapse in patients with PR3-ANCA vs MPO-ANCA (HR 1.66, 95% CI 1.08, 2.54). The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.
Authors
Dhruti P. Chen, Claudia P. Aiello, DeMoris A. McCoy, Taylor Stamey, Jiajin Yang, Susan L. Hogan, Yichun Hu, Vimal K. Derebail, Eveline Y. Wu, J. Charles Jennette, Ronald J. Falk, Dominic J. Ciavatta
Abstract
CD4+ cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves’ orbitopathy (GO). However, little is known about therapeutic targeting CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mTORC1 inhibitor, in GO mouse model, in vitro and in refractory GO patients. In the adenovirus-induced model, rapamycin significantly decreased the incidence of orbitopathy. This was accompanied by reduction of CD4+ CTLs, and improvement of inflammation, adipogenesis and fibrosis in orbits. CD4+CTLs from active GO patients showed upregulation of mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and clinical activity score in steroid-refractory GO patients. Single-cell RNA sequencing revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.
Authors
Meng Zhang, Kelvin K.L. Chong, Zi-yi Chen, Hui Guo, Yu-feng Liu, Yong-yong Kang, Yang-jun Li, Ting-ting Shi, Kenneth Ka Hei Lai, Ming-qian He, Kai Ye, George J. Kahaly, Bing-yin Shi, Yue Wang
Abstract
Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses are linked with T1D development. Mutations within IFIH1, encoding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing non-obese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice that may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared to NOD mice. While NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I interferons, pancreatic-infiltrating TNF+ macrophages, IFN-γ+ CD4+ T cells, and perforin+ CD8+ T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared to wild-type MDA5. Our results suggest dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.
Authors
Samuel I. Blum, Jared P. Taylor, Jessie M. Barra, Ashley R. Burg, Qiao Shang, Shihong Qiu, Oren Shechter, Aleah R. Hayes, Todd J. Green, Aron M. Geurts, Yi-Guang Chen, Hubert M. Tse
Abstract
The efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic gene expression subset would show the most significant clinical improvement. 84 participants with dcSSc were randomized to receive abatacept or placebo for 12 months. RNA-seq was performed on 233 skin paired biopsies at baseline, 3- and 6-months. Improvement was defined as a 5 point or >20% change in modified Rodnan skin score (mRSS) between baseline and 12 months. Samples were assigned to intrinsic gene expression subset (inflammatory, fibroproliferative, or normal-like). In the abatacept arm, change in mRSS was most pronounced for the inflammatory (p<0.001) and normal-like (p=0.03) subsets relative to placebo. Participants on placebo remained in their molecular subset while inflammatory participants treated with abatacept moved toward normal-like. The CD28 costimulation pathway decreased in patients that improved on abatacept (FDR=5.88x10-4) and was specific to the inflammatory subset (FDR=0%). Patients in the inflammatory subset had elevation of the CD28 costimulation pathway at baseline relative to fibroproliferative (p = 0.0026) and normal-like (p=0.0001) participants. There was a correlation between improved ΔmRSS and baseline expression of the CD28 costimulation pathway (R=-0.62, p=0.02). This study provides an example of precision medicine in SSc clinical trials.
Authors
Bhaven K. Mehta, Monica E. Espinoza, Jennifer M. Franks, Yiwei Yuan, Yue Wang, Tammara Wood, Johann Gudjonsson, Cathie Spino, David A. Fox, Dinesh Khanna, Michael L. Whitfield
Abstract
Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis–associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis–associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications — TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen.
Authors
Nathan Richoz, Zewen K. Tuong, Kevin W. Loudon, Eduardo Patiño-Martínez, John R. Ferdinand, Anaïs Portet, Kathleen R. Bashant, Emeline Thevenon, Francesca Rucci, Thomas Hoyler, Tobias Junt, Mariana J. Kaplan, Richard M. Siegel, Menna R. Clatworthy
Abstract
Leukocyte Adhesion Deficiency Type-1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common β-chain of the ß2 integrin family (CD18). The most prominent clinical symptoms are profound leukocytosis and high susceptibility to infections. At the same time, LAD-1 patients are prone to develop autoimmune diseases, but the molecular and cellular mechanisms that result in coexisting immunodeficiency and autoimmunity are still unresolved. CD4+FOXP3+ regulatory T cells (Treg) are known for their essential role in preventing autoimmunity. To understand the role of Treg in LAD-1 development and manifestation of autoimmunity we generated mice specifically lacking CD18 on Treg (CD18Foxp3), resulting in defective LFA-1 expression. Here we demonstrate a crucial role of LFA-1 on Treg to maintain immune homeostasis by modifying T cell – dendritic cell (DC) interactions and CD4+ T cell activation. Treg-specific CD18 deletion did not impair Treg migration into extra-lymphatic organs but resulted in shorter interactions of Treg with DC. In vivo, CD18Foxp3 mice developed spontaneous hyperplasia in lymphatic organs, and diffuse inflammation of the skin and in multiple internal organs. Thus, LFA-1 on Treg is required for the maintenance of immune homeostasis.
Authors
Tanja Klaus, Alicia S. Wilson, Elisabeth Vicari, Eva Hadaschik, Matthias Klein, Sara Salome Helbich, Nadine Kamenjarin, Katrin Hodapp, Jenny Schunke, Maximilian Haist, Florian Butsch, Hans C. Probst, Alexander H. Enk, Karsten Mahnke, Ari Waisman, Monika Bednarczyk, Matthias Bros, Tobias Bopp, Stephan Grabbe
Abstract
Vogt-Koyanagi-Harada (VKH) disease is an important refractory uveitis mediated by pathological T cells (TCs). Tofacitinib (TOFA) is a Janus kinases (JAKs) targeted therapy for several autoimmune diseases. However, the specific pathogenesis and targeted therapeutics for VKH remain largely unknown. Based on single-cell RNA sequencing and mass cytometry, we present the first multimodal high-dimensional analysis to determine a comprehensive human immune atlas of VKH patients undergoing TOFA therapy in the context of subset composition, gene signatures, enriched pathways, and intercellular interactions. VKH patients are characterized by TCs polarization from naive to effector and memory subsets, altogether with accrued monocytes, upregulated cytokines and JAK-STAT signaling pathways. In vitro, TOFA reversed Th17/ regulatory T-cell (Treg) imbalance and inhibited IL-2-induced STAT1/3 phosphorylation. TOFA alleviated VKH symptoms by restoring pathological TCs polarization and functional marker expression and downregulating cytokine signaling and lymphocyte function. Remarkably, inflammation-related responses and intercellular interactions decreased after TOFA treatment, particularly in monocytes. Notably, we identified two inflammation- and JAK-associated monocyte subpopulations that were strongly implicated in VKH pathogenesis and mechanisms involved in TOFA treatment. Here, we provide a novel JAK-targeted therapy for VKH and elaborate on the possible therapeutic mechanisms of TOFA, expanding our knowledge of VKH pathological patterns.
Authors
Xiuxing Liu, Qi Jiang, Jianjie Lv, Shizhao Yang, Zhaohao Huang, Runping Duan, Tianyu Tao, Zhaohuai Li, Rong Ju, Yingfeng Zheng, Wenru Su
Abstract
Therapeutics that inhibit IL-6 at different points in its signaling pathway are in clinical use yet whether the immunologic effects of these interventions differ based on their molecular target is unknown. We performed short-term interventions in individuals with type 1 diabetes using anti-IL-6 (siltuximab) or anti-IL-6 receptor (IL-6R; tocilizumab) and investigated the impact of this in vivo blockade on T cell fate and function. Immune outcomes were influenced by the target of the therapeutic intervention (IL-6 versus IL-6R) and by peak drug concentration. Tocilizumab reduced IL-6-driven STAT3 phosphorylation, ICOS expression on T follicular helper cell populations and TCR-driven STAT3 phosphorylation. Siltuximab reversed resistance to regulatory T cell-mediated suppression and increased TCR driven pSTAT3, and production of IL-10, IL-21 and IL-27 by T effectors. Together these findings indicate that the context of IL-6 blockade in vivo drives distinct T cell intrinsic changes that may influence therapeutic outcomes.
Authors
Cate Speake, Tania Habib, Katharina Lambert, Christian Hundhausen, Sandra Lord, Matthew J. Dufort, Samuel O. Skinner, Alex Hu, MacKenzie Kinsman, Britta E. Jones, Megan D. Maerz, Megan Tatum, Anne M. Hocking, Gerald T. Nepom, Carla J. Greenbaum, Jane H. Buckner
Abstract
BACKGROUND Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under “sub-immunogenic” conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol.METHODS A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71–specific (Cit-Vim–specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate.RESULTS DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim–specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181–treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim–specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.CONCLUSION The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.TRIAL REGISTRATION Anzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDING Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported by European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287.
Authors
Amee Sonigra, Hendrik J. Nel, Pascale Wehr, Nishta Ramnoruth, Swati Patel, Karin A. van Schie, Maxwell W. Bladen, Ahmed M. Mehdi, Joanne Tesiram, Meghna Talekar, Jamie Rossjohn, Hugh H. Reid, Frederik E. Stuurman, Helen Roberts, Phillip Vecchio, Ian Gourley, Mark Rigby, Stephane Becart, Rene E.M. Toes, Hans Ulrich Scherer, Kim-Anh Lê Cao, Kim Campbell, Ranjeny Thomas
No posts were found with this tag.
